Interferon-gamma is a lymphokine produced by activated T-lymphocytes and by large granular lymphocytes. It has antiviral, antitumor and immunomodulatory activities and is of potential clinical value. However, together with its positive biological activities, IFN-gamma has been shown to provoke undesirable effects and to be involved in the development of autoimmune diseases. Thus, IFN-gamma was present in newly diagnosed diabetic children and in muscle biopsies from patients with polymyositis. It was also found to cause exacerbation of autoimmune diseases such as multiple sclerosis and psoriasis.
It is therefore necessary to find ways to eliminate or antagonize the undesirable activities or effects of IFN-gamma endogenously formed in excess or exogenously administered, and particularly to block its action for controlling the progression of autoimmune processes.
In U.S. Pat. No. 4,897,264 of the same applicant three different types of human IFN-gamma receptors were described. The various receptors were isolated from different cells by extraction followed by affinity chromatography on an immobilized IFN-gamma column. The receptors were shown to bind IFN-gamma. They were further used as antigens to immunize mice for the obtention of polyclonal antibodies that blocked selectively the binding of IFN-gamma to some cells and not to others. They may also be used alone or together with the antibodies and/or IFN-gamma as immunosuppressants in autoimmune diseases. In U.S. Ser. No. 07/436,328, now abandoned monoclonal antibodies against the human IFN-gamma receptor were disclosed which blocked the binding of IFN-gamma to its receptor and inhibited the biological activity of IFN-gamma.
One of the effective ways of neutralizing the activity of a hormone or cytokine is to provide a soluble form of its receptor, that binds the protein outside the cell and blocks its activity. It is not necessary to use the whole receptor. A fragment of the receptor which contains the binding-site of the hormone or cytokine, e.g. an extracellular soluble fragment of the receptor will be able to block effectively its biological activity.